Project Summary/Abstract Visual experience begins with electrical responses of retinal photoreceptors. Only light detected by rods and cones can be analyzed by higher visual centers to alter our behavior. It is therefore essential that we understand how photoreceptors convert light into changes in membrane potential and how the mechanism of transduction is modulated in steady illumination. Although research during the last 30 years has clarified many features of photoreceptor biochemistry and physiology, most of this work has been done on rods, even though cones respond over a much wider range of intensities and are more important for visual perception. Cones have the remarkable ability to continue to respond even in bright light; unlike rods, cones never saturate no matter how strong the background illumination. Cones can continue to adjust sensitivity so that it remains proportional to ambient illumination, maximizing the detection of contrast even in light bleaching a significant fraction of the visual pigment. Moreover background light accelerates the recovery of the cone response, enhancing the sensitivity of the visual system to change and motion when light is no longer limiting. An understanding of adaptation is essential to any effort to replace visual function in degenerated retina with some form of extrinsic light detector. We cannot hope to restore the ability of vision to operate over an extensive range of light intensities unless sensitivity and response kinetics can be made to adapt to the ambient light intensity. Failure of photoreceptors to adapt or recover normally can lead to genetically inherited retinal diseases including night blindness, bradyopsia, Oguchi disease, and Leber?s amaurosis. For this reason, the Retinal Disease Program of the NEI has as one of its program objectives to ?analyze the mechanisms underlying light adaptation and recovery following phototransduction?. The goal of this research is to understand the effects of steady background light and bleaching on sensitivity and response recovery in mammalian cones, in order to test mechanisms previously postulated for rods and to reveal major gaps in our understanding. These experiments will exploit an unusually bright LED-based optical stimulator and transgenic animals to investigate basic properties of mammalian cone physiology; and to combine measurements of sensitivity modulation by bleaching and steady background light into a comprehensive explanation of light adaptation.